Toma et al. (2003): β-carotene supplementation in patients radically treated for stage I-II head and neck cancer: Results of a randomized trial

Reference ↗
Title	β-carotene supplementation in patients radically treated for stage I-II head and neck cancer: Results of a randomized trial
Topic	Vitamin A (beta-carotene)
Author	Toma, S, Bonelli, L, Sartoris, A, Mira, E, Antonelli, A, Beatrice, F, Giordano, C, Benazzo, M, Caroggio, A, Cavalot, AL, Gandolfo, S, Garozzo, A, Margarino, G, Schenone, G, Spadini, N, Zibordi, F, Balzarini, F, Serafini, I, Miani, P, Cortesina, G
Year	2003
Journal	Oncology Reports
DOI	https://doi.org/10.3892/or.10.6.1895

Brief summary

This study examined patients with head and neck cancer, half of whom took beta-carotene (i.e. a precursor of vitamin A) daily for three years and the control arm took nothing. There were no significant differences between the two arms in terms of overall survival, time to disease progression and incidence of recurrence or second primary tumors. A positive aspect of this study was the large sample size and the fact that the two arms did not differ in important characteristics at the beginning of the study. On the negative side, however, many patients stopped taking beta-carotene over time.

In dieser Studie wurden Patienten mit Kopf-Hals-Tumor untersucht, von denen die eine Hälfe drei Jahre lang täglich Betacarotin (d.h. eine Vorstufe von Vitamin A) und der Kontrollarm nichts einnahm. Die beiden Gruppen wiesen keine bedeutsamen Unterschiede bezüglich des Gesamtüberlebens, des Zeitraums bis zum Fortschreiten der Krankheit und bezüglich der Auftretenshäufigkeit von Rezidiven oder zweiten Primärtumoren auf. Positiv an dieser Studie war die große Stichprobe und dass sich die beiden Arme zur Beginn der Studie hinsichtlich wichtiger Merkmale nicht unterschieden. Negativ ist jedoch, dass sehr viele Patienten über die Zeit hinweg die Betacarotin-Einnahme abgebrochen haben.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	No
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	2

Study characteristics

Inclusion criteria	- Histologically confirmed HNSCC classified as stage I or II baccording to criteria of American Joint Committee on Cancer and radically treated with surgery and/or radiotherapy - Performance status 0-2 - Adequate liver, kidley, cardiac function
Exclusion criteria	- Cancer treated by chemotherapy - Previous invasive cancer at any side - Patients over 70 years (due to expected increasing prevalence of competing causes of death and potential low contribution to follow-up)
N randomized	218
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis, ITT Analysis
Specifications on analyses	ITT analysis for all 3 outcomes strictly overlapped with secondary analysis (PP), therefore only ITT analysis presented by authors
Countries of data collection	NI
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline Follow-up, median (range) per arm: - intervention: 61 (1-116) month - control: 58 (1-123) month

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Head and Neck Cancers
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage
Specifications on cancer stages	N (%) per arm: - intervention: 77 (74) stage I, 27 (26) stage II - control: 72 (65.5) stage I, 38 (34.5) stage II
Comorbidities	NI
Current cancer therapies	Surgery, Radiation therapy
Specifications on cancer therapies	Randomization within 1 month after assessment of complete response to treatment
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	N (%) per arm: - intervention: 94 (90.4) male, 10 (9.6) female - control: 99 (90) male, 11 (10) female
Age groups	Adults (18+)
Age groups specification	Median (range) per arm: - intervention: 60 (31-74) - control: 61 (31-75)

Arms

Compliance to treatment (62% in beta-carotene arm) largely different among patients enrolled in different participating institutions,

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	106
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2 patients excluded from all analyses
Drop-out reasons	Not separated by arm: 3/4 (no further information obtained after randomization), 1/4 (randomized twice)
Intervention	Beta-Carotene
Dosage and regime	75mg daily (orally), cycles of 3 months & then 1 month break + dose reduction and/or discontinuation of beta-carotene if grade II toxicity (repeatedly) reported
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	1,095
Side effects / Interactions	Skin toxicity (N = 4), mucositis (N = 1)

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	110
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	2 patients excluded from all analyses
Drop-out reasons	Not separated by arm: 3/4 (no further information obtained after randomization), 1/4 (randomized twice)
Intervention	None
Dosage and regime	NA
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	1,095
Side effects / Interactions	NI

Outcomes

OS (Overall Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	Baseline + every 2 months (for 3 years), then every 4 months (up to the 5th year), then twice a year
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall - No significant differences in 10-year survival rate between intervention and control arm (p=0.20) - Relative risk not significant (no p-value reported)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

DFS (Disease-Free Survival)

Outcome type As specificed by the authors	Secondary
Outcome specification	10-year DFS
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall - No significant differences in 10-year DFS rate between intervention and control arm (p=0.56) - Relative risks for DFS not significant (no p-value reported)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Tumor progression

Outcome type As specificed by the authors	Secondary
Outcome specification	Incidence of second primary tumors (SPT) and/or recurrence
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall - No significant differences in incidence of SPT between intervention and control arm (no p-value reported) - Relative risks for recurrence and/or SPT not significant (no p-value reported)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	NI
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis
- Reasons for insufficient sample size based on power analysis
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?